MEK Inhibitors: KE Duncan , LY Chang and M Patronas REVIEW a New Class of Chemotherapeutic Agents with Ocular Toxicity

1 2 1 MEK inhibitors: KE Duncan , LY Chang and M Patronas REVIEW a new class of chemotherapeutic agents with ocular toxicity

Abstract A new class of chemotherapeutic agents, MEK As MEK inhibitors progress through clinical inhibitors, has recently been developed and is trials and into the general patient population, proving to be an effective treatment for a eye care professionals should be aware of these number of cancers. A pattern of ocular adverse medications and their potential ocular toxicity events has followed these drugs through to recognize complications early and preserve clinical trials and their association with vision where possible. We report two cases of retinopathy is only just beginning to be MEK inhibitor-associated retinal toxicity as well recognized. We present two cases of MEK as a review of the current literature on these inhibitor-associated retinopathy followed by a medications and their ocular toxicity. review of the current literature on ocular toxicity associated with MEK inhibitors. Case 1 Patients undergoing treatment with MEK inhibitors appear to have high rates of multi- A 51-year-old female presented for an eye exam focal serous retinal detachments as well as prior to starting a clinical trial with a MEK retinal vein occlusions. We present the first inhibitor for metastatic ovarian cancer. Her vision report of cystoid macular edema associated with was 20/25 OU with a normal dilated fundus MEK inhibitor use. The mechanism of these exam. The patient returned for a repeat exam adverse events is still unclear though they seem 2 weeks after initiating MEK 162 at 45 mg PO BID. to be related to oxidative stress and blood retinal She had no visual complaints, however, vision 1Department of barrier breakdown. Management of the ocular was 20/40 OD and 20/25 OS. Retinal exam Ophthalmology and Visual toxicity can range from observation to topical revealed multifocal creamy yellow deep retinal Sciences, University of Maryland School of treatments or intravitreal injections. Fortunately lesions (Figure 1a). Optical coherence tomography Medicine, Baltimore, most ocular adverse events appear to be self- (OCT) revealed thickening and elevation of the MD, USA limited and do not require discontinuing the retinal pigment epithelium (RPE) at these locations MEK inhibitor. Discontinuation or decreased (Figure 2a). Fluorescein angiography (FA) showed 2University of Maryland dosing of MEK inhibitors may be reserved for early hyperfluorescence and late staining of the School of Medicine, cases of severe sight-threatening ocular toxicity. lesions in the right eye (Figure 3) and no Baltimore, MD, USA Eye (2015) 29, 1003–1012; doi:10.1038/eye.2015.82; abnormalities in the left eye. Since the lesions were Correspondence: published online 5 June 2015 not vision threatening, it was recommended that KE Duncan, Department of she continue the medication at the same dose with Ophthalmology and Visual fi Introduction close monitoring of the retinal ndings. The Sciences, University of patient returned in 2 weeks for repeat exam at Maryland School of Retinal toxicity has been associated with the which time the lesions had decreased in size. Medicine, 419 West recent use of a promising class of drugs that has Redwood Street, Suite 479, Her vision returned to baseline and the lesions had Baltimore, MD 21201, USA been developed for the treatment of metastatic almost completely disappeared at 1-month follow- Tel: +1 443 421 6062; cancer. These drugs inhibit the mitogen- up (Figures 1b and 2b). Fax: +1 410 328 1178. activated protein kinase/extracellular signal- CT scan 2 months into therapy revealed that E-mail: [email protected] regulated kinase (MAPK/ERK) kinase, also her cancer had a partial response with decrease known as the MEK enzyme. Despite significant in the size and number of metastases. At last Received: 9 November 2014 Accepted in revised form: ocular toxicity associated with these exam, 6 months after starting the medication, 14 April 2015 medications, very little information on this topic there had been no recurrence of retinal Published online: is present in the ophthalmologic literature. pathology. 5 June 2015 MEK inhibitors KE Duncan et al 1004

Figure 1 Case 1 fundus photography. (a) Multifocal deep retinal lesions appearing 2 weeks after initiating MEK inhibitor therapy. (b) Improvement in retinal lesions 1 month after initiating MEK inhibitor therapy.

Figure 2 Case 1 optical coherence tomography (OCT). (a) Thickening and elevation of the neurosensory retina and RPE in the area of the retinal lesions noted 2 weeks after initiating MEK inhibitor therapy. (b) Resolution of ﬁndings on OCT 1 month after initiating MEK inhibitor therapy.

Case 2 was 20/20 OD and 20/60 OS with normal intraocular pressure. Retinal exam and OCT revealed cystoid macular A 58-year-old male with metastatic melanoma since 2008 edema (CME) in the left eye (Figure 4a). FA showed late presented to the ophthalmology clinic with complaints of petalloid leakage in the left macula and mild staining of blurred vision from the left eye for 3 weeks. He had been the left optic nerve head (Figure 5). The patient had no started on Trametinib, the only FDA-approved MEK history of diabetes, uveitis, macular degeneration, eye inhibitor, 8 months prior to presentation. Visual acuity surgery, vein occlusions, or any other etiology to explain

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his macular edema. He was started on Pred Forte and visual acuity to 20/20. Following a slow taper of the Acular QID OS and on follow-up 6 weeks later he showed topical anti-inﬂammatory drops, the patient noticed slight complete resolution of the CME (Figure 4b) with return of blurring of the vision 1 week after discontinuation of the treatment. OCT revealed early recurrence and the treatment was re-initiated and the edema subsequently resolved. The patient is being maintained on a daily drop of Pred Forte to prevent recurrence.

Literature review

This article aims to review the available data on MEK inhibitor ocular toxicity, discuss its pathogenesis, and provide recommendations for management. The mitogen- activated protein kinase (MAPK) pathway is an important signal transduction pathway that controls cellular proliferation.1 The pathway includes a series of protein kinases (RAS, RAF, MEK, and ERK), which phosphorylate and activate one another, ultimately resulting in the activation of transcription factors in the cell nucleus that influence gene transcription and subsequently cellular proliferation (Figure 6). Dysregulation of this pathway is commonly found in human cancers. Mutations in the pathway occur most commonly in the RAS and RAF protein kinases. RAS mutations have been isolated in 63% of pancreatic cancers, 19% of non-small cell lung cancers, and 36% of colorectal and thyroid cancers.2 RAF mutations have been found in 69% of papillary thyroid cancers, 59% of melanomas, 18% of colorectal cancers and 14% of liver Figure 3 Case 1 fluorescein angiography in the right eye 3,4 2 weeks after initiating MEK inhibitor therapy. (a) Hyperfluore- cancers. As MEK is immediately downstream from RAS sence of retinal lesions was noted in the early phase. (b) Late and RAF in the signal transduction pathway, it has staining of the retinal lesions was noted in the late phase. become a highly attractive chemotherapeutic target.

Figure 4 Case 2 optical coherence tomography (OCT) of the left eye. (a) Cystoid macular edema. (b) Resolution of cystoid macular edema after 6 weeks of Pred Forte and Acular.

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Figure 5 Case 2 ﬂuorescein angiography (FA). Early (a), middle (b), and late (c) phases demonstrating late petalloid leakage of the left macula and staining of the left optic nerve head.

PD098059 was the first MEK inhibitor developed in the first MEK inhibitor to be approved by the FDA for the 1995. Due to poor pharmacokinetics and solubility, its use treatment of metastatic or unresectable melanoma in May in vivo was limited.5 CI-1040 was the first to enter clinical 2013. It remains the only FDA-approved MEK inhibitor trials in 2000.2,6 Since that time, at least 13 different MEK available at this time. inhibitors have been developed and evaluated in clinical As MEK inhibitors progress through clinical trials, trials. Recent clinical trials have used MEK inhibitors numerous drug toxicities have been identified. Similar to alone and in combination with other chemotherapeutic other chemotherapeutic agents, the most common agents to treat a variety of cancers including melanoma, adverse events reported have been diarrhea, nausea, rash, – ovarian cancer, leukemia, lymphoma, thyroid cancer, and weakness.7 13 Unique to MEK inhibitors, however, is colorectal cancer, non-small cell lung cancer, biliary the identification of high rates of ocular toxicity emerging cancer, and pancreatic cancer and so on.2 Trametinib was in these clinical trials.

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Figure 6 The RAS/RAF/MEK/ERK signal transduction pathway. Extracellular signaling ligands bind to receptor tyrosine kinases in the cell membrane. This results in activation of RAS, which in turn activates RAF. RAF phosphorylates and activates MEK. MEK phosphorylates and activates ERK. Once activated, ERK translocates to the nucleus where it binds to transcription factors to stimulate cell growth and proliferation. Mutations resulting in abnormal activation of this pathway may contribute to many human cancers.

CI-1040 In the phase II clinical trial for CI-1040, no partial or complete responses were observed therefore further CI-1040 was the first MEK inhibitor to enter clinical trials development of CI-1040 was terminated due to poor in 2000. The phase I trial enrolled 77 patients with locally antitumor activity.7 advanced or metastatic cancer who had failed conventional therapy or for whom there was no established life-prolonging therapy available. The study PD-0325901 enrolled patients with 13 different tumor types, with the A third MEK inhibitor, PD-0325901, has been developed most frequent being colorectal, non-small cell lung, and the results of the first clinical study were published in exocrine pancreatic, melanoma and kidney. About 59.6% 2010. Though structurally similar to CI-1040, PD-0325901 of patients experienced one or more adverse events is 50 times more potent at inhibiting MEK, has better related to therapy, though 98% were grade 1 or 2 in solubility, and increased metabolic stability.10 severity. There were no reported ocular adverse events. The phase I trial of PD-0325901 enrolled 66 patients About 66 of these patients were assessed for response to treatment and almost 30% achieved stabilization of with advanced breast, colorectal, non-small cell lung disease lasting a mean of 5.5 months.8 cancer, and melanoma. Seven patients (10.6%) developed Given the success and tolerable side effect profile transient blurred vision while taking PD-0325901. Of demonstrated in the phase I study, CI-1040 was further these seven, one patient reportedly developed optic evaluated with a phase II study in which more continuous neuropathy and two patients developed retinal vein and increased dosing was used. Sixty-seven patients with occlusion after 4 months of therapy. The decision was breast, colon, non-small cell lung, and pancreatic cancers made to amend the study protocol to add glaucoma, fi were enrolled in the study. Visual changes were reported ocular hypertension, and any other signi cant ocular in six (8.9%) patients. The authors describe these as abnormality to the study’s exclusion criteria. In addition, ‘transient blurring and altered light perception.’ One the dosing schedule was adjusted (5 days on/2 days off, patient had an abnormal retinal exam that subsequently instead of continuous dosing). Despite these changes, a returned to normal after stopping the medication. Vision third patient developed retinal vein occlusion after changes resolved within 1 day, with the exception of one 9 months of therapy. At that time, further enrollment in patient whose vision changes persisted for 2 weeks. All the study was stopped due to retinal toxicity.10 patients resumed treatment after visual changes resolved In spite of the drug toxicity, antitumor activity and none of the patients experienced a recurrence of appeared promising. Fifty-eight patients were evaluated visual symptoms.9 for drug efficacy. Twenty-three patients had stable

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disease after two rounds of therapy and three melanoma None of the patients that developed ocular toxicity were patients had partial responses.10 restarted on the medication. Visual acuity in the patient with retinal vein occlusion improved with anti-VEGF 14 AZD6244 injections. Reduction in tumor burden was seen in 10% of patients enrolled in the study.14,15 The phase I clinical trial of the free-base suspension of High response rates to GSK1120212 among patients AZD6244 was published in 2008 and enrolled 57 patients with malignant melanoma, especially those with BRAF with numerous types of advanced cancer for which there mutations, were demonstrated by this study and later 1,11 was no proven curative or life-prolonging therapy. confirmed in a phase II trial. Two cases of central serous Transient and reversible blurred vision was reported in retinopathy and no cases of retinal vein occlusion were seven patients (12%). Adjei et al11 report that reported in the phase II trial.16 A phase III trial ophthalmologic examinations in these patients were randomized 322 patients with BRAF mutant melanoma to unrevealing. Nine patients in this study achieved stable treatment with GSK1120212 vs standard chemotherapy. disease for ≥ 5 months. One patient with malignant They found that the progression-free survival was melanoma had 70% shrinkage of his tumors before 4.8 months in the MEK inhibitor group vs 1.5 months in developing brain metastasis.11 the standard chemotherapy group. Nineteen (9%) of the A phase I study was also conducted for an oral capsule formulation of AZD6244 to compare its bioavailability, patients receiving GSK1120212 in this trial reported efficacy, and safety to the initial formulation. About 10 of ocular adverse events, most being blurred vision. One ‘ the 59 (16.9%) patients enrolled reported ophthalmologic patient was described as developing reversible ’ adverse events. Blurred vision was the most common chorioretinopathy. There were no reports of retinal vein symptom, though diplopia, dry eye, eyelid edema, occlusion.17 Efficacy data from these clinical trials increased lacrimation, visual disturbance, and scleral prompted the FDA approval of GSK1120212 for patients hemorrhage were also reported. The authors state that with BRAF mutant melanoma. there were no patterns of abnormalities identified on ophthalmologic exams of these patients.12 Fifty-five RO5126766 patients were evaluated for antitumor activity of the drug. Ten patients (18.2%) achieved stable disease for RO5126766 was the first in the class of dual RAF/MEK ≥ 16 weeks. One patient, a 30-year-old female with inhibitors to enter clinical trials. The phase I trial enrolled malignant melanoma, had a complete response. Her 52 patients with a large variety of advanced tumors. melanoma had progressed despite six cycles of Ocular toxicities were reported in 26 patients (50%), with chemotherapy prior to enrolling in this study. At the time 22 patients reporting blurred vision. Through the course of last evaluation, she had no recurrence of disease 2 years of this study, the authors recognized an emerging pattern 12 after completing 15 months of AZD6244. of blurred vision among patients enrolled in this as well as other MEK inhibitor trials and began to implement GSK1120212 more thorough ophthalmologic evaluations. In doing so, they were able to identify 10 cases of serous retinal GSK1120212, which goes by the generic name Trametinib detachments on OCT imaging. This represents 38% of and trade name Mekinist (GlaxoSmithKline, Research patients with ocular adverse events. The authors note that Triangle Park, NC, USA), is the first FDA-approved MEK patients were not routinely evaluated with OCT from the inhibitor. On 29 May 2013, Trametinib was approved for beginning of the trial and therefore rates of serous retinal the treatment of patients with unresectable or metastatic detachment are likely underestimated in their data. All of melanoma with BRAF V600E or V600K mutations.13 the ocular symptoms reversed spontaneously or with GSK1120212 was studied in a phase I multicenter clinical trial, which enrolled 206 patients with advanced temporary interruption of systemic drug therapy. The solid tumors or lymphoma. Of note, exclusion criteria authors recommend that comprehensive ophthalmologic included history of retinal vein occlusion, central serous assessments, including visual acuity, intraocular pressure retinopathy, or glaucoma diagnosed within 1 month of measurement, fundoscopy, and OCT imaging, be starting the clinical trial. Ocular adverse events were implemented in future MEK inhibitor trials. reported in 31 patients (15%), including 3 patients who Of the 52 patients enrolled in this phase I trial, there developed central serous retinopathy and 1 patient who were 3 partial responses, 16 patients with stable disease at developed a retinal vein occlusion. All cases of central 16 weeks, and 2 patients with stable disease for 41 year. serous retinopathy were documented with OCT and All partial responses occurred in patients with malignant resolved after the patients were taken off the drug. melanoma.18

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MEK 162 detachments with MEK inhibitor use. All three of the patients described developed subfoveal neurosensory MEK 162 is currently in phase II of clinical trials. As retinal detachments within 1 month of initiating drug awareness of MEK inhibitor-associated retinopathy has spread among the oncology community, ophthalmic therapy. Two of the three patients also developed anterior adverse events are receiving more attention. Recently in uveitis. All ocular adverse events were self-limited and all the Annals of Oncology, Urner-Block et al19 thoroughly patients remained on the study drug, though dosing was 22 evaluated 32 patients receiving treatment with MEK 162 lowered in one patient. for ophthalmologic complications. Every patient was sent to an ophthalmologist for a complete dilated eye exam including OCT imaging of the retina prior to starting Mechanism of ocular toxicity treatment, 15 days into treatment and monthly from there As the ocular toxicity associated with MEK inhibitors is a on. Nineteen of the 32 (59%) patients were found to have relatively new discovery, very little is known about the retinopathy described as multifocal grayish-yellow round mechanism of these ocular events. The majority of ocular lesions associated with serous retinal elevation. Only 8 of toxicities reported with MEK inhibitors have occurred at these 19 (42%) patients were symptomatic. Those that were symptomatic described mild blurred vision. All the level of the retina with the two most common and patients had marked resolution of the lesions and blurred sight-threatening events being retinal vein occlusion and fl vision 2–6 weeks after starting treatment. This resolution subretinal uid accumulation. occurred regardless of whether the patients continued the The occurrence of retinal vein occlusion, which resulted drug at the same dose or discontinued the drug. The in termination of PD-0325901 clinical trials, prompted 23 authors concluded that there is a very high rate of Huang et al to establish an animal model to investigate MEK inhibitor-associated retinopathy even among the mechanism of this adverse event. Intravitreal asymptomatic patients. The retinopathy was generally injections of PD-0325901 were administered to rabbits at mild, self-limited, and may not require discontinuation of various doses. At higher doses, all rabbits developed treatment.19 retinal vein occlusion within 24 h. At 1 week post injection, the rabbits developed retinal edema, vascular attenuation, and retinal detachments. Oral PD-0325901 MEK inhibitors in the ophthalmology literature was administered to rats after which retinal gene Despite high rates of ocular adverse events described in expression analysis was conducted. No retinal occlusive MEK inhibitor clinical trials, very few cases have been events were seen in the rats; however, there were described in the ophthalmologic literature. significant changes in retinal gene expression. An 20 Velez-Montoya et al reported three cases of central upregulation of genes involved in oxidative stress, blood serous retinopathy in patients enrolled in different MEK retinal barrier breakdown, inflammatory response, as well inhibitor clinical trials. Each of these cases resolved within as coagulation cascade activation were observed. The days of stopping the drug without complications.20 authors hypothesized that MEK inhibitors result in a A case report in 2013 described a 54-year-old female combination of oxidative stress and a pro-thrombotic who developed multifocal central serous-like retinopathy state, which together increase the risk for retinal vein after starting a MEK inhibitor for malignant melanoma. occlusion.23 The patient presented for baseline eye exam prior to Subretinal fluid accumulation in the absence of retinal starting Dabrafenib (BRAF inhibitor) and Trametinib vein occlusions has also been a common finding in (MEK Inhibitor) and was found to have 20/20 vision OU patients treated with MEK inhibitors. RPE cells are with normal exam findings. She returned 3 weeks after responsible for maintaining the outer blood retinal barrier starting the medications with visual acuity of 20/60 OD fl 24 and 20/50 OS. Dilated fundus exam and OCT were and preventing subretinal uid accumulation. Jiang et al fl suggestive of multifocal neurosensory retinal discovered the presence of aquaporin 1, a uid transport detachments. Visual acuity improved and subretinal fluid channel, in RPE cells. They also demonstrated that the resolved within 9 days of stopping both the medications. MEK/ERK pathway was involved in the regulation of 24 The MEK inhibitor was restarted 1 month later at a lower aquaporin density within the RPE. The high incidence of dose with recurrence of subretinal fluid and worsening serous retinal detachments described in patients taking visual acuity. These changes again resolved after stopping MEK inhibitors suggests that MEK inhibition may alter the MEK inhibitor for the second time.21 the permeability of the RPE and thus disrupt its ability to More recently, McCannel et al22 published a case series serve as a barrier that prevents subretinal fluid of patients who developed neurosensory retinal accumulation.

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Conclusions/Recommendations Table 1 The most common adverse events and ocular adverse events in MEK inhibitor clinical trials In this paper, we described two patients who developed retinal abnormalities during a course of treatment with Clinical trial Most common Frequency of ocular adverse events adverse events MEK inhibitors. Our findings are similar to those published in the ophthalmologic literature. MEK CI-1040 Phase 1 Diarrhea (33%) None (0%) inhibitors present a promising new option in the field of Asthenia (23%) oncology but preliminary data suggest that these Rash (14%) Nausea (12%) medications are associated with high rates of ocular Vomiting (11%) toxicity (Table 1). More information is needed to fully CI-1040 Phase 2 Diarrhea (57%) 6 patients (8.9%) characterize these toxicities and their pathogenesis. The Nausea (52%) development and utilization of these medications may Fatigue (48%) Rash (25%) result in an opportunity as well as challenge for Edema (22%) ophthalmologists to diagnose and manage ocular PD-0325901 Phase 1 Rash (79%) 7 patients (10.6%) complications in this patient population. Awareness of Fatigue (61%) this class of medications and their ocular adverse effects Diarrhea (55%) among eye care professionals is the first step in managing Nausea (38%) Edema (26%) ocular complications. AZD6244 Phase 1 Rash (75%) 7 patients (12.2%) fl Numerous cases of subretinal uid and RPE (oral suspension) detachments associated with MEK inhibitors have been Diarrhea (61%) self-limited despite continuing systemic drug therapy. Nausea (44%) As in Case 1 and in previously reported cases, the RPE Fatigue (39%) Edema (33%) detachments were asymptomatic, not vision threatening, AZD Phase 1 Fatigue (68%) 10 patients (16.9%) and resolved without local treatment or alteration of (oral capsule) systemic drug therapy. In asymptomatic patients, it may Rash (63%) be appropriate to continue the medication with more Nausea (54%) Diarrhea (48%) frequent follow-up to assess for worsening or Edema (43%) improvement of retinal pathology. Should the retinal GSK1120212 Phase 1 Rash (83%) 31 patients (15.0%) changes result in significant decrease in visual acuity Diarrhea (80%) without resolution over a period of 2–3 months, dose Fatigue (42%) reduction or temporarily stopping the medication to Edema (33%) Nausea (29%) allow resolution should be considered. Restarting the GSK1120212 Phase 2 Rash (75%) 2 patients (2.0%) medication at a lower dose once the ocular adverse effects Diarrhea (52%) have resolved has been successful in preventing Nausea (30%) recurrence in many cases. Edema (29%) The patient in Case 2 developed CME, a complication Pruritis (27%) GSK1120212 Phase 3 Rash (57%) 19 patients (9.0%) that has not been previously reported in association with Diarrhea (43%) MEK inhibitors. Since this CME resolved completely with Fatigue (26%) anti-inflammatory regimen of topical steroid and NSAID, Edema (26%) this regimen may be considered as a management for Dermatitis (19%) retinal edema while continuing chemotherapy. Similar to RO5126766 Rash (94%) 22 patients (42.3%) Elevated creatinine fi 22 the ndings of McCannel et al, in which two-thirds of phosphokinase patients had anterior uveitis, CME is likely inflammatory levels (56%) in etiology, justifying the use of topical or injectable anti- Diarrhea (52%) inflammatory medications in these cases. Blurred vision (42%) Retinal vein occlusion has been a rare but serious event Edema (31%) associated with these medications that has the potential to result in permanent vision loss. In patients who have developed retinal vein occlusion, resulting visual acuity as well as the patient’s response to treatment should be steroid injections has proven useful in reducing macular weighed. Consideration should be given to stopping the edema and improving vision to varying degrees. These MEK inhibitor in these cases to prevent a second occlusive treatments can be used in cases in which vein occlusion event from occurring in the same eye or in the fellow eye. and macular edema are believed to be an adverse events The treatment of vein occlusions with anti-VEGF and related to the MEK inhibitor. In addition, monitoring for

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systemic complications related to a suspected 7 Wang D, Boerner SA, Winkler JD, LoRusso PM. Clincal pro-thrombotic state is also advised. experience of MEK inhibitors in cancer therapy. Biochim – In summary, we recommend that patients who will be Biophys Acta 2007; 1773(8): 1248 1255. 8 Lorusso PM, Adjei AA, Varterasian M, Gadgeel S, Reid J, started on a MEK inhibitor have a baseline retina Mitchell DY et al. Phase I and pharmacodynamic study of the fi examination with OCT and close follow-up in the rst oral MEK inhibitor CI-1040 in patients with advanced month of initiating the new drug as retinal changes may malignancies. J Clin Oncol 2005; 23: 5281–5293. be asymptomatic. In patients being treated with these 9 Rinehart J, Adjei A, LoRusso P, Waterhouse D, Hecht R, medications that present with ocular symptoms, dilated Natale R et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small cell fundus exam should be completed to look for retinal lung, breast, colon, and pancreatic cancer. J Clin Oncol 2004; abnormalities. OCT should be obtained to rule out 22: 4456–4462. pathology at the level of the RPE. FA should be utilized to 10 LoRusso PM, Krishnamurthi SS, Rinehart JJ, Nabell LN, monitor leakage and inflammation-related side effects. Malburg L, Chapman P et al. Phase I pharmacokinetic and Patients on MEK inhibitors should be followed regularly pharmacodynamic study of the oral MAPK/ERK kinase to evaluate for ocular toxicity, especially in the first year inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer Res 2010; 16: 1924–1937. of treatment. Management of retinal disease may vary 11 Adjei AA, Cohen RB, Franklin W, Morris C, Wilson D, depending on the suspected etiology and severity of Molina JR et al. Phase I pharmacokinetic and symptoms. Treatment can range from close observation of pharmacodynamic study of the oral, small-molecule asymptomatic pigment epithelial or neurosensory retinal mitogen-activated protein kinase kinase 1/2 inhibitor detachments to topical anti-inflammatory drops for iritis AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol 2008; 26(13): 2139–2146. or retinal edema, to intravitreal anti-VEGF or steroids for 12 Banerji U, Camidge DR, Verheul HMW, Agarwal R, Sarker macular edema from retinal vein occlusion. Although D, Kaye S et al. The first-in-human study of the hydrogen patients may be reluctant to discontinue a potentially sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor life-prolonging treatment as these patients have often AZD6244 (ARRY-142886): a phase I open-label multicenter failed to respond to all other chemotherapeutic agents, trial in patients with advanced cancer. Clin Cancer Res 2010; 16(5): 1613–1623. discontinuation or decreased dosing of medication should 13 Trametinib—Food and Drug Administration. http://www. be considered for cases of severe sight-threatening ocular fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ toxicity. ucm354478.htm. Accessed 30 May 2013. As utilization of MEK inhibitors increases in the field of 14 Infante JR, Fecher LA, Falchook GS, Nallapareddy S, oncology, more extensive ophthalmologic evaluation of Gordon MS, Becerra C et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK these patients will be needed to better understand inhibitor trametinib: a phase 1 dose-escalation trial. Lancet pathophysiology and long term prognosis for patients Oncol 2012; 13(8): 773–781. who develop ocular adverse events related to these 15 Falchook GS, Lewis KD, Infante JR, Gordon MS, Vogelzang medications. NJ, Demarini DJ et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 – Conflict of interest dose-escalation trial. Lancet Oncol 2012; 13(8): 782 789. 16 Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman The authors declare no conflict of interest. JA et al. Phase II study of the MEK1/MEK2 inhibitor trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a References BRAF inhibitor. J Clin Oncol 2013; 31(4): 482–489. 17 Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, 1 Renouf DJ, Valzquez-Martin J, Simpson R, Siu L, Bedard P. Milhem M et al. Improved survival with MEK inhibition Ocular toxicity of targeted therapies. J Clin Oncol 2012; 30: in BRAF-mutated melanoma. N Engl J Med 2012; 367(2): 3277–3284. 107–114. 2 Zhao Y, Adjei AA. The clinical development of MEK 18 Martinez-Garcia M, Banerji U, Albanell J, Bahleda R, Dolly S, Inhibitors. Nat Rev Clin Oncol 2014; 11: 385–400. Kraeber-Bodere F et al. First-in-human, phase I dose- 3 Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B et al. escalation study of the safety, pharmacokinetics, and BRAF mutation in papillary thyroid carcinoma. J Natl Cancer pharmacodynamics of RO5126766, a first-in-class dual Inst 2003; 95(8): 625–627. MEK/RAF inhibitor in patients with solid tumors. 4 Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S Clin Cancer Res 2012; 18(17): 4806–4819. et al. Mutations of the BRAF gene in human cancer. Nature 19 Urner-Bloch U, Urner M, Stieger P, Galliker N, Winterton N, 2002; 417(6892): 949–954. Zubel A et al. Transient MEK inhibitor-associated 5 Cheng Y, Zhang G, Li G. Targeting MAPK pathway in retinopathy in metastatic melanoma. Ann Oncol 2014; 25: melanoma therapy. Cancer Metastasis Rev 2013; 32(3-4): 1437–1441. 567–584. 20 Velez-Montoya R, Olsen J, Petrash M, Messersmith W, 6 Akinleye A, Furqan M, Mukhi N, Ravella P, Delong L. MEK Mandava N, Oliver S. 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21 Schoenberger SD, Kim SJ. Bilateral multifocal central 23 Huang W, Yang AH, Matsumoto D, Collette W, serous-like chorioretinopathy due to MEK Inhibition for Marroquin L, Ko M et al. PD0325901, a mitogen-activated metastatic cutaneous melanoma. Case Rep Ophthalmol Med protein kinase kinase inhibitor, produces ocular toxicity in rabbit animal model of retinal vein occlusion. J Ocul 2013; 2013: 673796. Pharmacol Ther 2009; 25: 519–530. 22 McCannel TA, Chmielowski B, Finn RS, Goldman J, 24 Jiang Q, Cao C, Lu S, Kivlin R, Wallin B, Chu W et al. MEK/ Ribas A, Wainberg ZA et al. Bilateral subfoveal neurosensory ERK pathway mediates UVB-induced AQP1 retinal detachment associated with MEK inhibitor downregulation and water permeability impairment in use for metastatic cancer. JAMA Ophthalmol 2014; 132: human retinal pigment epithelial cells. Int J Mol Med 2009; 1005–1009. 23: 771–777.

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